Economic Evaluation of Pneumococcal Vaccines for

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vaccination would cost on average about 83 000, 60 000 and 52 000 per QALY gained .... Table A.1: Estimated burden of disease and costs in 2016 in Belgium related to S. pneumoniae in .... nearest un it). Scenario. PPV23. PCV13. PCV13+. PPV23. PCV13+. PPV23 ...... Willingness to pay for a QALY (1000 euro).
Economic Evaluation of Pneumococcal Vaccines for Adults Aged Over 50 Years in Belgium: Supporting information Lander Willem1 , Adriaan Blommaert1 , Germaine Hanquet2 , Nancy Thiry2 , Joke Bilcke1 , Heidi Theeten3 , Jan Verhaegen4 , Herman Goossens5 , Philippe Beutels1,6,*

1 Centre for Health Economics Research & Modeling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium. 2 KCE - Belgian Health Care Knowledge Centre, Brussels, Belgium. 3 Center for the Evaluation of Vaccination (CEV), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium. 4 Department of Clinical Microbiology, Universitair Ziekenhuis Leuven, Leuven, Belgium. 5 Laboratory of Medical Microbiology (LMM), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium. 6 School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia. * [email protected]

Abstract Streptococcus pneumoniae causes a high disease burden including pneumonia, meningitis and septicemia. Both a polysaccharide vaccine targeting 23 serotypes (PPV23) and a 13-valent conjugate vaccine (PCV13) are indicated for persons aged over 50 years. We developed and parameterized a static multi-cohort model to estimate the incremental cost-effectiveness and budget-impact of these vaccines at different uptake levels. Using three different vaccine efficacy scenarios regarding non-invasive pneumococcal pneumonia and extensive uni- and multivariate sensitivity analyses, we found a strong preference for PPV23 over PCV13 in all age groups at willingness to pay levels below e300 000 per quality adjusted life year (QALY). PPV23 vaccination would cost on average about e83 000, e60 000 and e52 000 per QALY gained in 50-64, 65-74 and 75-84 year-olds, whereas for PCV13 this is about e171 000, e201 000 and e338 000, respectively. Strategies combining PPV23 and PCV13 vaccines were most effective but generally less cost-effective. When assuming a combination of increased duration of PCV13 protection, increased disease burden preventable by PCV13 and a 75% reduction of the PCV13 price, PCV13 could become more attractive in 65 years of age in Belgium by the Superior Health Council (CSS/HGR) around the same time. However, the uptake of PPV23 has always been low in this group. Pneumococcal conjugate vaccines (PCV) are available in Europe since 2001. Only the 13-valent PCV (PCV13) has been approved for adults in 2011 against invasive pneumococcal disease and in 2015 against all pneumococcal pneumonia. PPV23 and PCV13 differ in the number of serotypes covered, the corresponding proportion of pneumococcal disease that they prevent, the type of immunity that is conferred and the price. In addition, the distribution of circulating PCV13 and PPV23 serotypes changed markedly in recent years as a result of universal PCV vaccination of infants (indirect effect or herd immunity through the subsequent use of PCV7, PCV13 and now PCV10 in infants) 1,2 . Overall pneumococcal disease rates in elderly have decreased over time in most settings as a net result of a decrease in disease caused by PCV13 serotypes, though a gradual increase in disease caused by non-PCV13 serotypes has been observed. The decision on which vaccine (and schedule) should be preferred in the elderly thus partly depends on the indirect effects of the infant PCV vaccination. The research presented in the main article addresses an economic evaluation, adopting a health care payer’s perspective. The costs and benefits of different vaccination strategies are compared with each other, including the current situation of low PPV23 vaccination coverage in the elderly. The considered vaccination strategies involve the administration of PPV23 alone, PCV13 alone, PCV13 followed by PPV23, different options for revaccination and different uptake levels (ranging 20-60%) in adults over 50 years. The main research questions are: What is the clinical impact of the vaccination strategies in terms of incremental number of hospitalizations, outpatient cases, fatalities and long term sequelae due to pneumococcal disease? What is the (incremental) cost-effectiveness of the vaccination strategies compared to each other? What is the budget impact of the vaccination strategies? This study was conducted as a Health Technology Assessment (HTA) for the Belgian Health Care Knowledge Centre (KCE) to assist policy making in Belgium 3 . The full text of the report can be found here. In this supplementary file, we present more details on the modeling results and inputs. A general study overview and the primary results are described in the main text.

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Contents Appendix A Estimated burden of disease and costs in Belgium by S. pneumoniae in 2016.

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Appendix B Avoided burden and cost-effectiveness

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Appendix C Sensitivity analysis

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Appendix D Budget-impact analysis

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Appendix E Parameter values and distributions

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Bibliography

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Appendix A

Estimated burden of disease and costs in Belgium by S. pneumoniae in 2016. This supplement presents the predicted burden of disease in Belgium of S. pneumoniae in 2016 with low PPV23 vaccine uptake (0.79% for 50-64 years, 2.46% for 65-74 year, 3.01% for 75-84 years and 2.48% for 85-105 years). We estimated to attain 5905 hospitalizations due to S. pneumoniae (with 3606 additional patients treated in ambulatory care), about 428 deaths and 4161 QALYs lost. The health care costs for treatment amount to about e33.7 million. The number of fatalities, and particularly those of pneumonia, is higher in older age groups, despite the decreasing size of each age group with increasing age. The number of hospitalizations and especially outpatients decline in the more advanced age groups, and this explains also the decreasing trend in costs by age group. More details can be found in Table A.1.

Table A.1: Estimated burden of disease and costs in 2016 in Belgium related to S. pneumoniae in adults 50 years and older. Results presented as the median of 1000 simulations, rounded to the nearest unit. Age Age group size

50-64 years

55-74 years

75-84 years

85-105 years

Total

2 233 358

1 022 444

720 255

288 423

4 264 480

Cases invasive pneumococcal pneumonia

275

224

228

199

926

Cases meningitis, total

29

11

12

10

62

Cases other invasive pneumococcal diseases

27

23

23

20

92

Cases hospitalized non-invasive pneumococcal pneumonia

1431

1169

1188

1036

4824

Total number of hospitalizations

1762

1427

1451

1265

5905

Cases outpatient non-invasive pneumococcal pneumonia

1517

778

822

489

3606

Cases meningitis, with long term hearing loss

3

1

1

1

6

Cases meningitis, with long term neurological sequelae

3

1

1

1

6

Deaths pneumococcal pneumonia

74

77

109

138

398

Deaths meningitis

4

1

3

5

13

Deaths other invasive pneumococcal diseases

4

4

4

5

17

Total number of deaths

82

82

116

147

428

Quality adjusted life years lost

1816

1078

802

465

4161

Quality adjusted life years lost (discounted)

1535

978

761

454

3727

Total direct health care cost in e

13 336 267

9 339 376

7 039 081

3 991 872

33 706 596

Total direct health care cost in e (discounted)

12 328 033

9 137 858

6 940 564

3 954 000

32 360 455

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Appendix B

Avoided burden and cost-effectiveness This supplement presents more details on the estimated cost-effectiveness and avoided burden of disease of vaccination scenarios for different age groups. We present the incremental results of each vaccination strategy comparing to the current situation or other scenarios. First, we present results based on the assumption that both vaccines have baseline efficacy against non-IPP for age groups 50-64 years, 65-74 years and 75-84 years (Table B.2-B.4). Next, we present the predicted avoided burden and costs of scenarios that are affected by the assumption that PPV23 has no efficacy against non-IPP (Table B.5-B.7). Details on the vaccine scenarios can be found in Table B.1.

Table B.1: Vaccination strategies defined by vaccine choice, schedule and uptake in different age groups. Scenario

50-64 years

55-74 years

75-84 years

85-105 years

Current situation (yearly means of the 2004, 2008 and 2013 five year accumulated uptake)

0.79% PPV23

2.46% PPV23

3.01% PPV23

2.48% PPV23

PPV23 (1)

25% PPV23

50% PPV23

60% PPV23

40% PPV23

PCV13 (2)

25% PCV13

50% PCV13

60% PCV13

40% PCV13

PCV13 + PPV23 (3)

(1) + (2)

(1) + (2)

(1) + (2)

(1) + (2)

PPV23 + revaccination

(1) + 15% PPV23 after 5 year

(1) + 25% PPV23 after 5 year

(1) + 25% PPV23 after 5 year

(1) + 20% PPV23 after 5 year

PVC13 + revaccination

(2) + 15% PPV23 after 5 year

(2) + 25% PPV23 after 5 year

(2) + 25% PPV23 after 5 year

(2) + 20% PPV23 after 5 year

PCV13 + PPV23 + revaccination

(3) + 15% PPV23 after 5 year

(3) + 25% PPV23 after 5 year

(3) + 25% PPV23 after 5 year

(3) + 20% PPV23 after 5 year

5

6

82 814 (83 728)

ICER = mean (cost) / mean (QALY)

1 897 853 (1 922 192)

Total medical cost discounted (e)

-21 723 637 (-21 723 637)

2 273 774 (2 304 334)

Total medical cost undiscounted (e)

Total vaccination costs (administration and purchase) discounted

239 (237)

Discounted QALY lost

14 (14)

288 (285)

Total deaths

Undiscounted QALY lost

11 (11)

1 (1)

Pneumococcal CAP deaths

1 (1)

Deaths other IPD

127 (126)

Outpatient pneumococcal CAP cases

Deaths meningitis

217 (218)

9 (9)

Pneumococcal CAP hospitalizations

9 (9)

Other IPD cases

current

Reference

Meningitis cases

PPV23

Scenario

201 172 (206 351)

-47 457 504 (-47 457 504)

1 814 202 (1 819 553)

2 141 852 (2 150 497)

227 (222)

275 (268)

14 (14)

13 (13)

1 (1)

1 (1)

202 (199)

269 (268)

6 (6)

5 (5)

current

PCV13

168 879 (171 883)

-69 858 085 (-69 858 085)

3 140 474 (3 130 975)

3 758 030 (3 754 478)

395 (388)

478 (470)

24 (24)

21 (20)

2 (2)

2 (2)

274 (270)

411 (410)

13 (13)

12 (12)

current

PCV13+ PPV23

301 246 (307 561)

-48 134 448 (-48 134 448)

1 242 621 (1 245 382)

1 484 256 (1 487 532)

156 (153)

190 (186)

10 (10)

9 (9)

1 (1)

0 (0)

146 (144)

194 (194)

4 (4)

3 (3)

PPV23

PCV13+ PPV23

125 313 (126 149)

-22 400 581 (-22 400 581)

1 326 272 (1 342 424)

1 616 178 (1 632 994)

168 (167)

203 (201)

10 (10)

8 (8)

1 (1)

1 (1)

71 (70)

142 (143)

7 (7)

7 (7)

PCV13

PCV13+ PPV23

113 132 (113 080)

-11 169 539 (-11 169 539)

662 624 (670 614)

907 389 (917 913)

93 (93)

117 (116)

7 (7)

6 (6)

1 (1)

1 (0)

28 (28)

86 (86)

5 (5)

4 (4)

PPV23

PPV23+ revac.

1 262 175 (1 290 100)

-24 001 146 (-24 001 146)

144 029 (144 161)

204 203 (204 526)

19 (19)

25 (24)

2 (2)

2 (2)

0 (0)

0 (0)

17 (17)

29 (29)

1 (1)

0 (0)

PCV13

PCV13+ revac.

136 910 (136 704)

-11 169 539 (-11 169 539)

543 429 (549 124)

753 607 (763 893)

78 (78)

98 (98)

6 (6)

5 (5)

1 (1)

0 (0)

16 (15)

66 (67)

5 (5)

4 (4)

PCV13+ PPV23

PCV13+ PPV23 + revac.

Table B.2: Avoided burden and cost-effectiveness of vaccination in 50-64 year olds (mean (median) based on 1000 simulations, rounded to the nearest unit)

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57 212 (57 716)

ICER = mean (cost) / mean (QALY)

2 340 219 (2 355 593)

Total medical cost discounted (e)

-19 545 248 (-19 545 248)

2 559 386 (2 575 999)

Total medical cost undiscounted (e)

Total vaccination costs (administration and purchase) discounted

301 (298)

Discounted QALY lost

29 (28)

337 (333)

Undiscounted QALY lost

Total deaths

2 (2)

25 (25)

Deaths other IPD

Deaths pneumococcal CAP hospitalizations

1 (1)

134 (132)

Outpatient pneumococcal CAP cases

Deaths meningitis

342 (344)

Pneumococcal CAP hospitalizations

7 (7)

14 (15)

Other IPD cases

current

Reference

Meningitis cases

PPV23

Scenario

171 344 (174 491)

-43 107 470 (-43 107 470)

2 034 813 (2 042 580)

2 268 919 (2 275 051)

240 (235)

272 (266)

25 (24)

23 (22)

1 (1)

1 (1)

180 (179)

349 (351)

8 (8)

4 (4)

current

PCV13

132 590 (134 364)

-63 617 697 (-63 617 697)

3 624 245 (3 613 952)

4 023 606 (4 014 425)

452 (447)

511 (503)

45 (44)

41 (40)

3 (3)

1 (1)

256 (254)

575 (574)

19 (20)

10 (10)

current

PCV13+ PPV23

281 970 (288 510)

-44 072 449 (-44 072 449)

1 284 026 (1 279 330)

1 464 220 (1 461 007)

152 (148)

174 (170)

17 (16)

16 (15)

1 (1)

0 (0)

122 (121)

232 (229)

5 (5)

3 (3)

PPV23

PCV13+ PPV23

88 929 (89 579)

-20 510 227 (-20 510 227)

1 589 432 (1 602 632)

1 754 687 (1 768 112)

213 (211)

239 (236)

20 (20)

18 (18)

2 (2)

1 (1)

76 (75)

226 (227)

11 (11)

6 (6)

PCV13

PCV13+ PPV23

86 217 (86 564)

-7 978 159 (-7 978 159)

550 574 (556 219)

703 101 (710 144)

86 (86)

102 (101)

12 (12)

10 (10)

1 (1)

1 (1)

27 (26)

101 (102)

6 (6)

3 (3)

PPV23

PPV23+ revac.

1 954 873 (2 005 960)

-17 143 496 (-17 143 496)

59 156 (57 756)

83 592 (81 846)

9 (9)

11 (11)

2 (2)

1 (1)

0 (0)

0 (0)

7 (7)

16 (15)

1 (1)

0 (0)

PCV13

PCV13+ revac.

104 198 (104 021)

-7 978 159 (-7 978 159)

442 472 (446 616)

569 559 (575 383)

72 (72)

85 (86)

10 (10)

9 (9)

1 (1)

1 (1)

15 (15)

78 (79)

6 (6)

3 (3)

PCV13+ PPV23

PCV13+ PPV23 + revac.

Table B.3: Avoided burden and cost-effectiveness of vaccination in 65-74 year olds (mean (median) based on 1000 simulations, rounded to the nearest unit)

8

52 147 (52 606)

ICER = mean (cost) / mean (QALY)

2 037 593 (2 048 091)

Total medical cost discounted (e)

-16 465 506 (-16 465 506)

2 190 270 (2 199 671)

Total medical cost undiscounted (e)

Total vaccination costs (administration and purchase) discounted

277 (275)

Discounted QALY lost

51 (51)

297 (294)

Total deaths

Undiscounted QALY lost

45 (45)

3 (3)

Deaths pneumococcal CAP

3 (3)

Deaths other IPD

161 (159)

Outpatient pneumococcal CAP cases

Deaths meningitis

422 (423)

Pneumococcal CAP hospitalizations

9 (9)

18 (18)

Other IPD cases

current

Reference

Meningitis cases

PPV23

Scenario

338 159 (325 811)

-36 383 438 (-36 383 438)

720 635 (759 370)

804 301 (846 006)

105 (109)

115 (118)

20 (21)

18 (18)

1 (2)

1 (1)

51 (53)

151 (159)

8 (8)

4 (4)

current

PCV13

155 395 (156 659)

-53 721 416 (-53 721 416)

2 400 162 (2 394 913)

2 610 605 (2 604 577)

330 (328)

356 (353)

63 (63)

56 (55)

4 (4)

3 (3)

188 (185)

505 (501)

22 (22)

11 (11)

current

PCV13+ PPV23

688 486 (701 802)

-37 255 910 (-37 255 910)

362 570 (345 028)

420 335 (401 840)

54 (52)

59 (58)

12 (12)

10 (10)

1 (1)

1 (1)

27 (21)

83 (78)

4 (4)

2 (2)

PPV23

PCV13+ PPV23

69 655 (70 189)

-17 337 978 (-17 337 978)

1 679 527 (1 668 893)

1 806 304 (1 799 159)

225 (223)

241 (239)

43 (42)

38 (38)

3 (3)

2 (2)

137 (132)

354 (350)

14 (14)

7 (7)

PCV13

PCV13+ PPV23

143 642 (143 834)

-4 497 254 (-4 497 254)

189 543 (191 253)

238 671 (240 687)

30 (30)

34 (34)

8 (8)

6 (6)

1 (1)

1 (1)

11 (11)

47 (47)

3 (3)

1 (2)

PPV23

PPV23+ revac.

4 058 817 (6 148 401)

-9 663 716 (-9 663 716)

16 478 (7 106)

19 739 (10 013)

2 (2)

3 (2)

1 (1)

1 (0)

0 (0)

0 (0)

2 (0)

4 (2)

0 (0)

0 (0)

PCV13

PCV13+ revac.

165 978 (165 633)

-4 497 254 (-4 497 254)

159 723 (162 038)

201 883 (204 520)

26 (26)

30 (30)

7 (7)

6 (6)

1 (1)

0 (0)

8 (7)

39 (39)

3 (3)

1 (1)

PCV13+ PPV23

PCV13+ PPV23 + revac.

Table B.4: Avoided burden and cost-effectiveness of vaccination in 75-84 year olds (mean (median) based on 1000 simulations, rounded to the nearest unit)

Table B.5: Avoided burden and cost-effectiveness of vaccination in 50-64 year olds focusing on outcomes differentially affected by assuming 0% PPV23 protection against non-IPP. Mean (and median) values are presented based on 1000 simulations, rounded to the nearest unit. Scenario

PPV23

PCV13+ PPV23

PCV13+ PPV23

PCV13+ PPV23

PPV23+ revac.

PCV13+ PPV23 + revac.

Reference

current

current

PPV23

PCV13

PPV23

PCV13+ PPV23

Pneumococcal CAP hospitalizations

91 (92)

340 (340)

249 (249)

72 (73)

53 (54)

48 (48)

Outpatient pneumococcal CAP cases

0 (0)

202 (199)

202 (199)

0 (0)

0 (0)

0 (0)

Deaths pneumococcal CAP

6 (6)

18 (18)

12 (11)

5 (5)

4 (4)

4 (4)

Total deaths

9 (9)

21 (21)

13 (12)

7 (7)

6 (6)

5 (5)

Undiscounted QALY lost

185 (186)

420 (415)

235 (229)

145 (146)

94 (94)

85 (85)

Discounted QALY lost

153 (154)

347 (342)

194 (188)

120 (120)

75 (75)

67 (68)

Total medical cost undiscounted (e)

1 544 001 (1 560 490)

3 350 223 (3 357 728)

1 806 222 (1 812 282)

1 208 371 (1 221 041)

715 758 (724 050)

646 305 (653 404)

Total medical cost discounted (e)

1 198 029 (1 211 728)

2 749 371 (2 754 083)

1 551 342 (1 552 508)

935 169 (946 770)

504 164 (510 044)

454 701 (459 934)

134 520 (133 754)

193 672 (195 888)

240 215 (247 945)

179 448 (178 542)

143 114 (142 471)

159 132 (158 365)

ICER = mean (cost) / mean (QALY)

Table B.6: Avoided burden and cost-effectiveness of vaccination in 65-74 year olds focusing on outcomes differentially affected by assuming 0% PPV23 protection against non-invasive CAP. Mean (and median) values are presented based on 1000 simulations, rounded to the nearest unit Scenario

PPV23

PCV13+ PPV23

PCV13+ PPV23

PCV13+ PPV23

PPV23+ revac.

PCV13+ PPV23 + revac.

Reference

current

current

PPV23

PCV13

PPV23

PCV13+ PPV23

Pneumococcal CAP hospitalizations

142 (145)

461 (463)

319 (320)

112 (114)

62 (63)

56 (57)

Outpatient pneumococcal CAP cases

0 (0)

180 (179)

180 (179)

0 (0)

0 (0)

0 (0)

Deaths pneumococcal CAP

15 (15)

35 (34)

20 (19)

12 (12)

8 (8)

7 (7)

Total deaths

19 (19)

40 (39)

21 (20)

15 (15)

10 (10)

9 (9)

Undiscounted QALY lost

221 (221)

445 (440)

224 (219)

173 (173)

82 (83)

74 (75)

Discounted QALY lost

197 (197)

393 (390)

197 (192)

154 (154)

70 (70)

63 (63)

Total medical cost undiscounted (e)

1 407 644 (1 422 650)

3 370 651 (3 377 205)

1 963 008 (1 964 573)

1 101 732 (1 115 574)

506 897 (513 110)

457 520 (462 632)

Total medical cost discounted (e)

1 231 614 (1 246 499)

2 995 547 (3 003 829)

1 763 934 (1 767 914)

960 734 (973 552)

387 714 (392 483)

349 445 (353 452)

93 164 (93 035)

154 073 (155 640)

214 884 (220 802)

127 148 (126 935)

108 886 (108 234)

121 233 (120 303)

ICER = mean (cost) / mean (QALY)

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Table B.7: Avoided burden and cost-effectiveness of vaccination in 75-84 year olds focusing on outcomes differentially affected by assuming 0% PPV23 protection against non-invasive CAP. Mean (and median) values are presented based on 1000 simulations, rounded to the nearest unit Scenario

PPV23

PCV13+ PPV23

PCV13+ PPV23

PCV13+ PPV23

PPV23+ revac.

PCV13+ PPV23 + revac.

Reference

current

current

PPV23

PCV13

PPV23

PCV13+ PPV23

Pneumococcal CAP hospitalizations

175 (178)

298 (299)

123 (123)

147 (145)

29 (29)

26 (27)

Outpatient pneumococcal CAP cases

0 (0)

55 (53)

55 (53)

4 (0)

0 (0)

0 (0)

Deaths pneumococcal CAP

28 (28)

41 (41)

13 (13)

23 (23)

5 (5)

5 (5)

Total deaths

34 (35)

49 (48)

14 (14)

28 (28)

6 (6)

6 (6)

Undiscounted QALY lost

195 (197)

274 (273)

78 (77)

159 (158)

28 (28)

26 (26)

Discounted QALY lost

182 (183)

253 (252)

71 (70)

148 (147)

24 (25)

22 (22)

Total medical cost undiscounted (e)

1 140 457 (1 153 939)

1 742 765 (1 744 464)

602 308 (605 272)

938 464 (934 312)

166 954 (168 459)

151 503 (152 679)

Total medical cost discounted (e)

1 025 739 (1 040 724)

1 563 189 (1 563 209)

537 451 (541 760)

842 555 (837 547)

130 001 (131 248)

117 838 (118 911)

85 001 (84 274)

206 160 (206 720)

514 585 (522 877)

111 806 (112 348)

178 542 (177 869)

196 832 (195 995)

ICER = mean (cost) / mean (QALY)

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Appendix C

Sensitivity analysis In addition to the exploration of three vaccine efficacy scenarios for non-IPP and a parametric sensitivity analysis based on Monte-Carlo sampling, we also explored model uncertainty though a uni- and multivariate sensitivity analysis. Unless stated otherwise, all results reported in this supplement were obtained with fully parameterized vaccine efficacy against non-IPP for both PCV13 and PPV23. We report results for WTP levels up to e350 000 per QALY gained, so when we say an option is unlikely the most beneficial at any WTP level, it is implied that this is for any WTP level up to e350 000 per QALY.

Univariate sensitivity analysis In the univariate (or one way) sensitivity of the input parameters on the effectiveness and cost-effectiveness of the different strategies, each assumption was tested while keeping all other parameters fixed. We tested 17 assumptions: Higher PPV23 protection against non-IPP by assuming the vaccine effectiveness ratio for non-IPP/IPD = 0.77 (instead of baseline 0.55) makes PPV23 vaccination more cost-effective, lowering the WTP level to about e40 000 per QALY for 65-84 year olds. PCV13 containing strategies are no longer the most beneficial over the entire WTP range considered. Five years of PCV13 protection followed by no protection does not dominate baseline PPV23 protection (with or without revaccination) targeted at 65-84 year olds and 50-64 year olds in those age groups when WTP exceeds e50 000 and e80 000 per QALY, respectively. PCV13 is unlikely to be the most cost-effective option at any WTP level considered. Minimum duration of PCV13 protection (i.e. 4 years fixed protection followed by rapid waning to no protection at 10 years) and baseline PPV23 protection, provides very similar results to those of the previous scenario. Maximum duration of PCV13 protection (i.e. 9 years fixed protection followed by slow waning to no protection at 20 years) and baseline PPV23 protection, lowers the WTP level at which strategies with PCV13 are retained in 50-74 year olds to about e250 000 - e275 000 per QALY. In 75-84 year olds, PCV13 is still not included as part of the most beneficial strategies at any WTP level considered. Age-independent PCV13 efficacy in all ages between 50-84 year old using the constant overall vaccine efficacy as reported in CAPITA and still 0% efficacy in >85 year olds, makes PCV13 unlikely to be the most cost-effective option in any age group at any WTP level considered. While this seems logical for those aged 50-64 years, it may sound counter-intuitive for older age groups. For 65-74 year olds, at a WTP around e350 000 per QALY, there is a clear difference between the baseline result and the result when assuming an age-independent 11

PCV13 vaccine efficacy. The tilting point of age-dependence is 72 years (average age CAPITA study), meaning that under the age-independence assumption, 65-72 year olds will have a lower PCV13 vaccine efficacy and 73-74 year olds will have a higher PCV13 vaccine efficacy. The 65-72 years however dominate the result of the age category 65-74, meaning that PCV13 scenarios become less attractive when assuming an age-independent PCV13 vaccine efficacy. For 75-84 year olds, the improved efficacy estimate lowers the certainty by which the PPV23-only strategies dominate PCV13 containing strategies over the range of WTP considered. When WTP exceeds e400 000, PCV13+PPV23 with revaccination is the strategy with the highest expected benefits. Two years of complete PPV23 protection followed by no protection and with baseline PCV13 vaccine protection, requires the WTP to exceed e90 000 for any PPV23 vaccination strategy to become cost effective. PCV13 is unlikely to be the most cost-effective option at any WTP level considered. Five years of PPV23 protection without waning followed by no protection and with baseline PCV13 vaccine protection, makes PPV23 yet more cost-effective compared to PCV13 for all age groups, and becomes overall more rapidly a more attractive strategy versus the current situation. This is especially the case in the age groups 65-74 and 75-84 years, from a WTP threshold of about e40 000 per QALY. PCV13 containing strategies are unlikely to be preferred in any age group. Five years of both PCV13 and PPV23 protection without waning followed by no protection is almost identical to the previous change. PPV23 is even more certain to be the most beneficial over the entire WTP range. Minimum serotype shift with a PCV13 serotype incidence decline of 10% per year, and baseline replacement (76%), makes vaccination options slightly more cost-effective. The age group of 65-84 years remains the most beneficial to subsidize pneumococcal vaccination using PPV23 from about e45 000 per QALY. In 50-64 year olds, vaccination with PPV23 becomes likely beneficial from a WTP of about e70 000, and from about e220 000 with PCV13+PPV23 with revaccination (e200 000 for 65-74 year olds). For 75-84 year olds PCV13 containing strategies are not selected as the most cost-effective. Maximum serotype shift with a PCV13 serotype incidence decline of 20% per year and baseline replacement (76%), echoes our baseline analyses though slightly less favorable towards vaccination. PPV23 is not likely cost-effective until WTP exceeds about e50 000 - e70 000 per QALY. PCV13 containing options are not likely to be the most cost-effective in any age group. Quick serotype relapse in which the PCV13 serotype incidence returns to the 2015 value within 7 years, all vaccination options become more attractive, and in particular PCV13 containing and PPV23 revaccination options for e230 000. Following the introduction of infant PCV10 in other countries, overall IPD did hardly decline though non-PCV10 types increased rapidly, most often driven by a 19A rise. If these trends would continue, overall disease incidence could increase above pre-vaccination levels, as observed in Finland in 2015, five years after PCV10 introduction 4 . Slow serotype relapse with the PCV13 serotype incidence returning to 2015 value within 15 years, all vaccination options become more attractive compared to the default settings, but 12

less so than in the “quick” relapse scenario described above. The most beneficial PCV13 containing scenario is PCV13+PPV23 with revaccination in the age groups 50-74 year olds (from e175 000). For 75-84 year olds, no PCV13 containing strategies are likely to be the most beneficial at any WTP level considered. Higher hospitalized pneumococcal pneumonia incidence by doubling the baseline incidence of pneumococcal pneumonia hospitalizations makes PPV23 vaccination of 50-84 year olds likely to be cost-effective at a WTP value of e50 000 per QALY gained. This is especially the case for 75-84 year and 65-84 year old groups from about e25 000 and e30 000 per QALY gained, respectively. In the age groups 50-64 years and 65-74 years, PCV13 containing strategies in combination with PPV23, tend to be the most cost-effective at a WTP per QALY exceeding e200 000 and e160 000, respectively. In 75-84 year olds, a PCV13 containing strategy seems never the most beneficial. Higher percentage of pneumococcal pneumonia in outpatient CAP (i.e. 27% 5 instead of 10.5%) makes all vaccination options more attractive, especially PPV23. We observed as most optimal with increasing WTP, as with most other scenarios, first the current situation, then PPV23 alone and subsequently with PPV23 revaccination is preferred. Finally from a WTP above e250 000, the most beneficial strategy for the age group 50-74 years is PCV13+PPV23 with revaccination but this is not the case for those over 75 years of age. PCV13 price reduction analysis shows that 25% to 50% reductions in the price of PCV13 makes little difference to the overall picking order of age groups and strategies. If we assume that PPV23 has 0% efficacy against non-IPP, PCV13 price reductions of 75% do have an effect. In that case, especially the age groups of 50-64 and 65-74 years are more likely to favor PCV13 containing strategies. The minimum WTP level at which PCV13 containing strategies are favored over PPV23 alone when the price is reduced by 25%, 50% and 75% is at about e250 000, e200 000 and e55 000 for 50-64 year olds and at about e250 000, e170 000 and e50 000 for 65-74 year olds. None of these price reductions show the highest expected benefits for a PCV13 containing strategy in 75-84 year olds below a WTP of e250 000 per QALY. In the age group 75-84 years, a price reduction of 75%, and assuming no protection of PPV23 against non-IPP, still only leads to the selection of PPV23 based strategies. The only strategy including a PCV13 component for this age group is PCV13+PPV23 with revaccination having the highest expected net benefits when WTP attains about e250 000 per QALY. PPV23 price reductions make PPV23 containing strategies more attractive. The current retail price of PPV23 (e28.46 per dose), as modeled throughout this analysis, is higher than in some other countries. For instance in France, the retail price in 2015 was e12.46 per dose. Price reductions are most influential for strategies that use multiple vaccine doses, but the single dose PPV23 strategy remains most cost-effective in 75-84 year olds. The incremental cost-effectiveness of revaccination with PPV23 over single dose PPV23 remains most cost-effective for 65-74 year olds. With a 75% reduction in PPV23 price, the mean ICERs for these strategies, depending on the inclusion or exclusion of an effect on non-IPP, become e20 000 - e37 000 and e37 000 - e48 000 per QALY gained, respectively. Higher PPV23 vaccine efficacy against IPD (82% versus 56% in the baseline) and non-IPP (43% versus 31% in the baseline), makes all PPV23 containing strategies more attractive. However, the influence of this variation is not very large and there is no change in the relative attractiveness of the different strategies. With this higher efficacy, the ICERs of increased PPV23 uptake for 50-64 year, 65-74 year and 75-84 year decline to about e55 000, e37 000 and e34 000, respectively if PPV23 protects against non-IPP, and e89 000, e61 000, 13

e56 000 if it does not. A 50% PPV23 price reduction would further make these values decline to e33 000, e21 000, e19 000 and e55 000, e37 000, e34 000, respectively. The price analysis shown in Figure C.1, illustrates the impact of increasing PCV13 price reductions (from top to bottom) for the age group 65-74 year olds. It indicates that from a 75% price cut, single dose PCV13 emerges as the most beneficial option for WTP values around e50 000 e100 000 per QALY. This is particularly the case when PPV23 is assumed to have 0% efficacy against non-IPP.

Multivariate sensitivity analysis In the multivariate sensitivity analyses, we simultaneously varied a number of assumptions and parameter choices discussed in the previous section. Numerous combinations can be made, though we point out some notable aspects in this section. The combination of PCV13 price reductions and a relapse in PCV13 serotypes that are not covered by the PCV10 vaccine from the childhood vaccination program in Belgium could change the prioritization of PPV23 over PCV13 for the ages 50-74 years. This finding is illustrated by a bivariate analysis shown in Figure C.2, showing the impact of increasing PCV13 price reductions (from top to bottom) with maximum duration of PCV13 protection, assuming normal (left hand side) and 50% higher pneumococcal pneumonia incidence (right hand side). Maximum duration of PCV13 protection is defined as 9 years fixed protection followed by slow waning to no protection at 20 years. Figure C.3 shows similar results under the assumption of a minimum duration of PCV13 protection (i.e.4 years fixed protection followed by rapid waning to no protection at 10 years). Both results were obtained assuming that PPV23 has 0% efficacy against non-IPP. These results indicate that from a 50% to 75% price cut, single dose PCV13 can emerge as the most beneficial option for WTP values around e50 000 - e100 000 per QALY gained, especially when we assume PCV13 has a long duration of protection. Under the assumption that PCV13 has a minimum duration of protection, the single PCV13 dose needs to be complemented with PPV23 revaccination to be the most cost-effective. If we simultaneously assume a relapse of PCV13 types in adults, the presence of PPV23 revaccination in the most beneficial options occurs earlier, i.e. for lower WTP values (results not shown).

14

200

250

300

1.5 1.0

Current situation PPV23 PCV13 PCV13 + PPV23

PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

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0

50

100

150

200

250

300

350

Willingness to pay for a QALY (1000 euro)

25% PCV13 price reduction

PPV23 provides no non-IPP protection 25% PCV13 price reduction

50

100

150

200

250

300

1.0 0.5 0.0

PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

1.5

Willingness to pay for a QALY (1000 euro)



350

Current situation PPV23 PCV13 PCV13 + PPV23

PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●



0

50

100

150

200

250

300

350

Willingness to pay for a QALY (1000 euro)

50% PCV13 price reduction

PPV23 provides no non-IPP protection 50% PCV13 price reduction



50

100

150

200

250

300

350

1.0 0.5

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

1.5

Willingness to pay for a QALY (1000 euro)

Current situation PPV23 PCV13 PCV13 + PPV23

0

0.5

350

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

1.5 1.0 0.5

150

Current situation PPV23 PCV13 PCV13 + PPV23

0

0.0

100

Probability highest net benefit

1.5 1.0 0.5 0.0

Probability highest net benefit

50

0.0



Probability highest net benefit

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0

Probability highest net benefit

PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

Probability highest net benefit

1.5 1.0 0.5 0.0

Probability highest net benefit

Current situation PPV23 PCV13 PCV13 + PPV23

Current situation PPV23 PCV13 PCV13 + PPV23

PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

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0

50

100

150

200

250

300

350

Willingness to pay for a QALY (1000 euro)

Willingness to pay for a QALY (1000 euro)

75% PCV13 price reduction

PPV23 provides no non-IPP protection 75% PCV13 price reduction

Figure C.1: Cost-effectiveness acceptability frontiers for the 65-74 year olds with increasing PCV13 price reductions, assuming baseline efficacy against non-invasive CAP for both vaccines (left hand side) or assuming PPV23 has 0% efficacy against non-invasive CAP while PCV13 has baseline efficacy (right hand side).

15

● ● ●

0.5



50

100

150

200

1

0

100

150

200

250

300

350

100

150

200

250

300



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

1



● ● ●

0.5

Probability highest net benefit



50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+



0

50

350





0

50

100

150

200

250

300

350

Willingness to pay for a QALY (1000 euro)

Willingness to pay for a QALY (1000 euro)

50% PCV13 price reduction

50% higher incidence of pneumococcal pneumonia 50% PCV13 price reduction AGES (years)

● ●





50

100

150

200

250

300

350



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

1



● ●

0



50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+

0.5

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

1



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

Probability highest net benefit

AGES (years) 50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+



50

AGES (years)

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac







STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+



0



50% higher incidence of pneumococcal pneumonia 25% PCV13 price reduction

1 0.5



0.5

● ●

25% PCV13 price reduction



0

●●

350

●●

0

Probability highest net benefit

300

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

Willingness to pay for a QALY (1000 euro)

AGES (years)



250



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

Willingness to pay for a QALY (1000 euro)

50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+



0



0



50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+



0.5

● ●

0

Probability highest net benefit

AGES (years)

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

Probability highest net benefit



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

1



0

Probability highest net benefit

AGES (years) 50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+





0

50

100

150

200

250

300

350

Willingness to pay for a QALY (1000 euro)

Willingness to pay for a QALY (1000 euro)

75% PCV13 price reduction

50% higher incidence of pneumococcal pneumonia 75% PCV13 price reduction

Figure C.2: Cost-effectiveness acceptability frontiers assuming quick serotype relapse and maximum duration of protection for PCV13 with decreasing PCV13 prices, assuming baseline and 50% higher incidence of pneumococcal pneumonia. All results are obtained assuming PPV23 has 0% efficacy against non-invasive CAP while PCV13 has baseline efficacy.

16

●●●●●

●●











50

100

150

200

1



0

50

100

150

200

250

300

350

● ●





0

100

150

200

250

300



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

1



50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+

0.5

0.5



Probability highest net benefit





350



● ● ●







0

50

100

150

200

250

300

350

Willingness to pay for a QALY (1000 euro)

Willingness to pay for a QALY (1000 euro)

50% PCV13 price reduction

50% higher incidence of pneumococcal pneumonia 50% PCV13 price reduction AGES (years)

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

●●

● ● ●





50

100

150

200

250

300

350

50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+



0



Probability highest net benefit



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

1

50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+

0.5

Probability highest net benefit



AGES (years)

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac



50



0





STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

1

50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+

AGES (years)

0

● ●

350







50% higher incidence of pneumococcal pneumonia 25% PCV13 price reduction





●●

25% PCV13 price reduction

●●●

0

● ●

Willingness to pay for a QALY (1000 euro)



0

Probability highest net benefit



300



Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

Willingness to pay for a QALY (1000 euro)

AGES (years) ●

250

STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

1

0



0





50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+

0.5

0.5

● ●

Probability highest net benefit



AGES (years)

Current situation for all ages PPV23 PCV13 PCV13 + PPV23 PPV23 + revac PCV13 + revac PCV13 + PPV23 + revac

1



STRATEGY

65−74 65−84 65+ 65−74&85+ 75−84 75+ 85+



0.5



0

Probability highest net benefit

AGES (years) 50−64 50−74 50−84 50+ 50−64&75−84 50−64&75+ 50−64&85+

● ●



0

50

100

150

200

250

300

350

Willingness to pay for a QALY (1000 euro)

Willingness to pay for a QALY (1000 euro)

75% PCV13 price reduction

50% higher incidence of pneumococcal pneumonia 75% PCV13 price reduction

Figure C.3: Cost-effectiveness acceptability frontiers assuming quick serotype relapse and minimum duration of protection for PCV13 with decreasing PCV13 prices, assuming baseline and 50% higher incidence of pneumococcal pneumonia. All results are obtained assuming PPV23 has 0% efficacy against non-invasive CAP while PCV13 has baseline efficacy.

17

The incidence of pneumococcal pneumonia is most influential in combination with changes in the severity of illness (such as all hospitalization and death rates). The joined impact of these factors is illustrated through the box plots shown in Figure C.4 and C.5. Both figures present the net benefit of the PPV23 and PCV13 vaccination strategy versus the current situation when doubling all incidences and assuming a willingness to pay of e35 000 per QALY gained. In Figure C.5, also a quick serotype relapse scenario is included as a change from the baseline. When the net benefits are positive for a given WTP value, the strategy is cost saving versus the current situation at that particular WTP level. The parametric uncertainty remains fully reflected by the position of the box plot versus 0 in each scenario considered. For ease of reference, we also added the box plots of the baseline settings for the PPV23 and PCV13 scenarios, in which vaccine efficacy against non-IPP is parameterized for both vaccines. When a given box plot is with its average or completely more to the right than another one (say if baseline PPV23 is more to the right than baseline PCV13), that means that the scenario it represents is on average or completely more beneficial. Figure C.4 and C.5 show results for each age group. The >85 year olds can be ignored given the 0% vaccine efficacy for this age group. Figure C.4 indicates that when PPV23 has some protection against non-IPP, doubling all incidences are sufficient to make PPV23 cost-saving at a WTP of e35 000 per QALY for all age groups 65 years of age, last estimates for 2015 (based on NRC, see Table E.10)

66% of all IPD

25% of all IPD

Retail price in Belgium 6

e28.40 per dose

e74.55 per dose

Recommended schedule in Belgium for adults 19-85 years of age with high risk of pneumococcal infection 7 .

Primovaccination PCV13 followed by PPV23 after minimum 8 weeks. Those previously vaccinated with PPV23: one PCV13 vaccination, at least 1 year after the last PPV23 dose. Re-vaccination with PPV23 every 5 years

Recommended schedule in Belgium for adults 50-85 years of age with comorbidity, and healthy adults 65-85 years of age in Belgium 7 .

Primovaccination PCV13 followed by PPV23 after minimum 8 weeks. Those previously vaccinated with PPV23: one PCV13 vaccination, at least 1 year after the last PPV23 dose. Booster: to be evaluated, based on supplementary data and the epidemiology after 5 years.

Recommended schedule in Belgium for adults >85 years of age 7 .

There is currently limited data on the effect of pneumococcal vaccination above 85 years of age. On an individual basis, taking into account the risk of pneumococcal infection and the evaluation of the immune response to the vaccine, the clinician may vaccinate a person above 85 years according to the recommended schedule (as above).

Table E.2: General overview of assumptions and model input parameter values: Vaccination Parameters Parameter

Values and distribution

Source/Reference

Current vaccine uptake

Varying from 1% to 20% by age group

Health Interview Survey data 8

Targeted vaccine uptake

See Table E.6

Targets sets in collaboration with panel of experts of the Belgian National Health Council

Vaccine efficacy (by age) and immunity waning of PCV13

See Table E.7 and E.8

CAPITA 9 , Frenck et al 10 , Van Werkhoven et al 11

Vaccine efficacy and immunity waning of PPV23

See Table E.7 and E.9.

Andrews et al 12 , Gutierrez et al 13 , Ochoa-Gondar et al. 14 , Vila-Corcoles et al. 15 .

Cost of vaccine administration

e11.7 (half a GP visit or e23.32/2)

Assumption based on expert panel

Cost per PCV13 dose

e74.55 current retail price, reduced prices explored in sensitivity analyses (25% stepwise reductions)

Belgian centre for pharmacotherapeutic information 6

Cost per PPV23 dose

e28.46 (2015 retail price), reduced prices explored in sensitivity analyses

Belgian centre for pharmacotherapeutic information 6

24

Table E.3: General overview of assumptions and model input parameter values: Epidemiological and demographical parameters Parameter

Values and distribution

Source/Reference

Size target group

Non-random, 2015

Eurostat 2015 population data

Vaccine serotype coverage: IPD

See Table E.10: PCV13 25%; PPV23 66%

NRC 2015 data for serogroups, van der Linden et al. 16 for serotype distribution within vaccine serogroups.

Vaccine serotype coverage: non-IPP

See Table E.11: PCV13 25% ; PPV23 51%

Benfield et al. 17

Incidence of outpatient pneumococcal disease (non-invasive)

Outpatient all-cause pneumonia incidence, outpatient CAP attributable to pneumococcal infections: 10.5% (95%CI 7.7-13.2). See Table E.12 for estimated incidence of outpatient pneumococcal pneumonia.

INTEGO 2013 R81 for incidence of all-cause pneumonia. Proportion of outpatient CAP due to pneumococcus: pooled estimate from Capelastegui et al and Holm et al 18,19

Incidence of hospitalised invasive pneumococcal disease

See Table E.13. All IPD assumed to be hospitalized

National Reference Centre (NRC), 2015, and Verhaeghen et al for the distribution of clinical syndromes 20 .

Incidence of hospitalised non-invasive pneumococcal pneumonia

Proportion of hospitalised adult pneumococcal CAP that is non-invasive: 82.7% (95%CI 80-86), based on IPD incidence data from Table E.13.

NRC for IPD incidence data. Pooled estimate of four studies for the proportion of hospitalised adult pneumococcal CAP that is non-invasive 21,14,22,23

Proportion of long term consequences of meningitis

Sequelae in 25.7% of meningitis survivors, assuming 12.9% hearing loss and 12.9% other neurological sequelae. In sensitivity analysis, we assume 20% hearing loss and 22% other neurological sequelae.

Jit 24 , Table E.19, Worsoe et al 25 and Ostergaard et al 26

Case fatality ratio of IPD

See Table E.14

Based on MZG/RHM deaths during hospitalisations, in IPD cases matched between NRC and MZG/RHM

Case fatality ratio (CFR) in outpatient pneumonia

1.7% for all ages (mean age study=74 years) / Sampled from beta distribution

Vila Corcoles et al 2009 27

Ratio CFR invasive versus non-invasive pneumonia

Adjusted hazard ratio for invasive versus non-invasive pneumonia 2.8 (1.6 - 5.1). Sampled from log-normal distribution

Capelastegui et al 2014 28 .

Indirect effect of PCV infant vaccination on PCV13 serotype incidence

Yearly decline of 16% (base case). see Table E.15 for sensitivity analyses.

SPIDNET 2010-15 analysis 29

Proportion of serotype replacement due to infant vaccination

Yearly compensation of 76.3% of the PCV13 decline (proportion of the PCV13 decline that is compensated by the non-PCV13 serotype increases). Scenarios for sensitivity analyses: Table E.15

SPIDNET 2010-15 analysis 29

Life expectancy

Belgian national institute of statistics (2014 last available year)

http://statbel.fgov.be table: “sterfte leven”

Background mortality

Belgian national institute of statistics (2014 last available year)

http://statbel.fgov.be table: “sterfte leven”

Table E.4: General overview of assumptions and model input parameter values: Costs of treatment Parameter

Values and distribution

Source/Reference

Hospitalisation cost

Table E.16

MZG/RHM linked with NRC

Out of hospital cost of outpatient pneumonia episodes

e80.9 per outpatient episode. Sensitivity analysis: e104.2 (adding a 2nd GP visit)

Derived from EU project GRACE, 30

Cost of long term consequences of meningitis

Hearing loss: Average e11 619 / 1st year and e1498 / year in following years. Neurological sequelae: e35 000 /year

KCE report n231 31

25

Table E.5: General overview of assumptions and model input parameter values: QALY utilities and discounting Parameter

Values and distribution

Source/Reference

QALY loss for hospitalised cases

Table E.17, PNEUMOCOST SURVEY France, uncertainty by bootstrapping, taking up QALY loss until 12 months after hospitalisation

PNEUMOCOST SURVEY France, personal communication of Gerard de Pouvourville, ESSEC, 2016 32

QALY loss for non-hospitalised pneumonia

Utility value QoL: 0.508 (0.442 - 0.575) sampled from normal distribution, applied during 8.5 days

Galante et al. 32

QALY loss long term consequences of meningitis

Utility weight for hearing loss: 0.635 (lifelong). Utility weight for neurological sequelae: 0.319 (lifelong). Sampled from normal distribution

Galante et al 32

UK population norms to use with Galante et al (average age: 31 years) disease-specific UK-derived utilities

0.93

Age group 25-35 years from Kind et al. 33

Discount rate for costs

0.03

Cleemput et al 34

Discount rate for health outcomes (life years, QALYs)

0.015

Cleemput et al 34

Table E.6: Vaccination strategies defined by vaccine choice, schedule and uptake in different age groups. Scenario

50-64 years

55-74 years

75-84 years

85-105 years

Current situation (yearly means of the 2004, 2008 and 2013 five year accumulated uptake)

0.79% PPV23

2.46% PPV23

3.01% PPV23

2.48% PPV23

PPV23 (1)

25% PPV23

50% PPV23

60% PPV23

40% PPV23

PCV13 (2)

25% PCV13

50% PCV13

60% PCV13

40% PCV13

PCV13 + PPV23 (3)

(1) + (2)

(1) + (2)

(1) + (2)

(1) + (2)

PPV23 + revaccination

(1) + 15% PPV23 after 5 year

(1) + 25% PPV23 after 5 year

(1) + 25% PPV23 after 5 year

(1) + 20% PPV23 after 5 year

PVC13 + revaccination

(2) + 15% PPV23 after 5 year

(2) + 25% PPV23 after 5 year

(2) + 25% PPV23 after 5 year

(2) + 20% PPV23 after 5 year

PCV13 + PPV23 + revaccination

(3) + 15% PPV23 after 5 year

(3) + 25% PPV23 after 5 year

(3) + 25% PPV23 after 5 year

(3) + 20% PPV23 after 5 year

Table E.7: PCV13 and PPV23 efficacy by age and IPD/non-IPP: baseline assumptions and sensitivity analysis 12,13,14,15,9,10,11 . Parameter mean and distribution are shown. PCV13

PPV23

Sensitivity analysis: increased PPV23 efficacy

Sensitivity analysis: Age-specific PCV13 efficacy

50-84 years

75.8% (47 to 90)

56% (40 to 68)

82% (69-90)

Scale to the hazard rate f HR = 1.058 (1.008 to 1.111) per year of age

>85 years non-IPP 50-79 years

0%

0%

0%

0%

41.1% (12.7%-62%)

30.8% (22%-37%)

43.1% (31%-52%)

Scale to the hazard rate f HR = 1.058 (1.008 to 1.111) per year of age

>80 years

0%

0%

0%

0%

IPD

26

Table E.8: Baseline and sensitivity PCV13 vaccine efficacy waning assumptions for 50-84 year olds based on a logistic waning using t50 : the time at which the current vaccine protection is reduced to 50% of initial vaccine efficacy and waning rate 12,13,14,15,9,10,11 . Scenario

Period of fixed vaccine protection

50% point (t50 )

Waning rate (k)

Base case

5

10 years

0.75

Min. scenario

4

6 years

0.75

Max. scenario

9

15 years

0.75

5 years only

5

-

-

Table E.9: Baseline and sensitivity PPV23 vaccine efficacy waning assumptions for 50-84 year olds based on a exponential waning using t50 : the time at which the current vaccine protection is reduced to 50% of initial vaccine efficacy. Scenario

Period of fixed vaccine protection

50% point (t50 )

Base case

2

1.5 years

2 years only

2

-

5 years only

5

-

Table E.10: Vaccine serogroups and serotypes in IPD cases (2015) among Belgian adults above 18 years of age, based on serogroup distribution reported by the Belgium National Reference Centre and serotype distribution from Van der Linden et al. 16 -: non applicable; *: serogroups from which at least one serotype is included in the vaccine. Vaccines

Serogroups* (observed counts)

Non-vaccine serotypes

Vaccine serotypes (estimated counts)

PCV13 and PPV23 (serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F)

37.4% (445)

13%

24.4% (241.9)

PPV23 only (serotypes 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F and 33F)

45.3% (552)

3.5%

41.8% (415.2)

PCV13 only (serotype 6A)

3.4% (38)

2.4%

1.0% (9.5)

All PCV13

40.8% (483)

-

25.3% (251.4)

All PPV23

82.7% (997)

-

66.2% (657.2)

No vaccine

13.9% (174)

-

32.9% (326.4)

Table E.11: Serotype distribution in IPD and non-invasive CAP among adults (>50 years) estimated in Belgium in 2015. *: counts are estimated by applying the van der Linden 16 serotype distribution to 2015 NRC serogroup counts; **: Based on Benfield et al 2013 17 extrapolated to 2015 based on annual serotype changes in IPD from SPIDNET network; CAP: community acquired pneumonia; IPD: Invasive pneumococcal disease; NRC: National Reference Centre. Serotype groups

Proportion of vaccine serotypes in IPD in Belgium, NRC (estimated counts)*

Proportion of vaccine serotypes non-invasive CAP (counts)**

PCV13 and PPV23 (serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F)

24.4% (241.9)

24.4% (64)

PPV23 only (serotypes 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F and 33F)

41.8% (415.2)

26.6% (69)

PCV13 only (serotype 6A)

1.0% (9.5)

0.3% (1)

All PCV13 serotypes

25.3% (251.4)

24.7% (64)

All PPV23 serotypes

66.2% (657.2)

51.1% (133)

Non-vaccine serotypes

32.9% (326.4)

48.7% (127)

Total

100% (993)

100% (260)

27

in

Table E.12: Incidence of outpatient all-cause and pneumococcal pneumonia per 100 000 persons (INTEGO 2013 R81 codes and 18,19 ). The estimated practice population is used as denominator. The yearly incidence rate of pneumonia is sampled from a beta(cases, denominator-cases) distribution to take uncertainty into account. Age group

Cases (2013)

Denominator (Practice population 2013)

All cause pneumonia (INTEGO)

Estimated pneumococcal pneumonia incidence

50-64 years

159

26555

598.8

57.0

65-74 years

75

11157

672.2

64.0

75-84 years

84

8325

1009.0

96.1

>85 years

63

4187

1504.7

143.3

Table E.13: Incidence of invasive pneumococcal disease (IPD) per 100 000 inhabitants in Belgium, 2015 National Reference Centre data corrected for underreporting 20,21,14,22,23 . * bacteraemia without focus, septicaemia, septic arthritis, peritonitis etc. Age group

Meningitis

Invasive pneumonia

Other IPD*

Total IPD

50-64 years

1.3

12.4

1.2

14.9

65-74 years

1.1

22.1

2.2

25.5

75-84 years

1.6

32.0

3.2

36.8

>85 years

3.6

69.6

7.0

80.2

Table E.14: Case fatality ratio of pneumococcal meningitis, pneumococcal septicemia and pneumococcal pneumonia as primary diagnosis, cases matched in MKG (ICD9) and NRC, 2007-12

Age group

Meningitis Cases Deaths

CFR (%)

Septicaemia Cases Deaths

CFR (%)

Pneumonia Cases Deaths

CFR (%)

50-64 years

68

9

13.2

368

61

16.6

509

31

6.1

65-74 years

43

5

11.6

298

49

16.4

404

40

9.9

75-84 years

18

4

22.2

348

64

18.4

404

58

14.4

>85 years

8

4

50.0

223

50

22.4

255

57

22.4

Table E.15: Serotype change scenarios informed by SPIDNET 2010-2015 data 29 . The serotype replacement is calculated as the relative non-PCV13 serotype increase divided by the relative decline of PCV13 serotypes. Based on SPIDNET data, we assumed a yearly increase of 4% of non-PCV13 types (that represented 75.3% of 2015 IPD incidence in Belgium) and an average decline of 16% of PCV13 types (24.7% of 2015 Belgian IPD incidence). This results in a yearly PCV13 serotype replacement of (4% * 75.3%) / (16% * 24.7%) = 76.3%. Scenario tag

Scenario description

PCV13 serotype decline (per year)

Replacement (per year)

Relapse

Baseline scenario

Average of SPIDNET of changes of non-PCV7 PCV13 serotypes

-16%

76.3%

no

Min. scenario

Rounded minimum yearly decline SPIDNET data of changes of non-PCV7 PCV13 serotypes

-10%

76.3%

no

Max. scenario

Rounded maximum yearly decline SPIDNET data of changes of non-PCV7 PCV13 serotypes

-20%

76.3%

no

Quick relapse

PCV13 serotype incidence returns to its 2015 value within 7 years

-16%

0%

With logistic curve: (t50%=5years, k=1)

Slow relapse

PCV13 serotype incidence returns to its 2015 value within 15 years

-16%

0%

With logistic curve: (t50%=10 years, k=0.5)

28

Table E.16: Mean costs of pneumococcal disease, per clinical syndrome (ICD9 primary diagnosis) in cases matched in MZG/RHM and NRC, 2007-12. Age group

Meningitis

Septicemia

Pneumonia

50-64 years

e7686

e8114

e5669

65-74 years

e8900

e6317

e5909

75-84 years

e9103

e5003

e1679

>85 years

e6973

e3137

e3466

Table E.17: QALY loss estimates of surviving hospitalized pneumococcal pneumonia patients (PNEUMOCOST-survey), up to 12 months, by age group and disease type. The QALY loss was negative for a minority of patients, which is expected given that the Quality of Life scores are compared to the population norms (from France) for an average person of the same age and risk group. Some patients in the study accumulated more (fractional) QALYs over a year than that the average person of the same age and risk group experiences. Age group

Disease

Average QALY loss (over 1 year)

Minimum QALY loss (over 1 year)

Maximum QALY loss (over 1 year)

Number patients

0-64 years

Non-invasive

0.0491

-0.3283

0.9692

69

0-64 years

Invasive

0.0203

-0.3288

0.5244

36

>65 years >65 years

Non-invasive

0.0679

-0.2713

0.8336

21

Invasive

0.1741

-0.2768

0.6710

28

of

Table E.18: Age-specific hospitalizations rate per 100 000 population for Pneumococcal Disease related ICD9 codes in MZG/RHM (Belgium 2013, first or secondary diagnostic field). Age group

Pneumococcal meningitis (ICD9 320.1)

Pneumococcal pneumonia (ICD9 481)

Pneumococcal septicaemia (ICD9 038.2)

50-64 years

0.7

13.8

4.4

65-74 years

1.6

41.9

15.0

75-84 years

1.3

60.8

19.8

>85 years

0.0

88.2

43.6

29

Table E.19: Frequency of sequelae in pneumococcal meningitis, per type. The proportion of survivors with each type of hearing loss is calculated by applying the proportion on all cases with audiometry to the total cases with hearing loss. *: including hearing loss. -: non applicable Ostergaard 2005 26

Kastenbauer 2003 35

Weisfelt 2006 36

Worsoe 2010 25

Aubertin 2006 37

Country

Denmark

Germany

The Netherlands

Denmark

France

Study period

1999-2000

1998-2002

1999-2003

2001-2003

Age group (mean)

>16 years years) 96 -

Adults (58 years)

>18 years

>18 years years)

243

144

105 (ICU)

30%

-

34.3%

Number adult survivors Any sequelae*

neurological

1984-2002 (61

>16 years years) 66 -

(50

Hearing loss >30dB

No definition

25.8%

21.8%

20.0%

No definition

Unilateral hearing loss >30dB

-

9.1%

6.8%

-

-

Bilateral >30dB

-

16.7%

15.0%

-

-

Hearing loss 30-70 dB

-

16.7%

11.3%

12.5%

-

Hearing loss 70-90db

-

4.5%

3.7%

-

4.5%

6.8%

Other: neurological

22.0%

unclear

unclear (multiple sequelae)

>70 dB: 10.4% >70 dB: 10.4% -

-

Hearing loss >90db

Other: palsies

-

4.6%

28%

-

-

Other: hemiparesis

-

-

7%

-

8.6%

Other: deficit

-

-

11%

-

-

hearing

loss

cranial nerve

focal cerebral

-

Table E.20: Case fatality ratio of pneumococcal disease (%) estimated in Belgium in 2015, by outcome. CAP: Community acquired pneumonia; IPD: Invasive pneumococcal disease, including invasive pneumonia; *: hospital deaths in cases matched in NRC and MZG/RHM; **: by applying a hazard ratio of 2.8 in invasive pneumococcal CAP vs. non-invasive; Age group

Inpatient IPD*

Inpatient non-invasive pneumococcal CAP**

Outpatient CAP 27

50-64 years

10.7%

2.2%

1.7%

65-74 years

12.6%

3.5%

1.7%

75-84 years

16.4%

5.1%

1.7%

>85 years

22.8%

8.0%

1.7%

pneumococcal

30

(56

Table E.21: Cost estimates for meningitis sequelae. Parameter

Value

Source/Reference

Proportion of hearing loss in meningitis survivors

12.9% in base case and 20% in sensitivity analysis

Jit et al. 24 and Worsoe et al. 25

Proportion of hearing loss requiring hearing aid (>30dB and 90dB)

25%

Kastenbauer Weisfelt 35,36

and

First year cost per hearing aid

e529

Hanquet et al 31

Cost for every following year per hearing aid

e339

Hanquet et al 31

First year cost per cochlear implant

e26,298

Hanquet et al 31

Cost for every following year per cochlear implant

e2577

Hanquet et al 31

Number of implants needed per hearing loss patient (average number of ears affected)

5/3

Kastenbauer Weisfelt 35,36

Average cost of treatment of hearing loss, per patient, first year

e11 618.75

Calculated from the respective proportion cost of hearing aid and cochlear implant.

Average cost of treatment of hearing loss, per patient, in the following years

e1497.5

Calculated from the respective proportion cost of hearing aid and cochlear implant.

Proportion other neurological sequelae in meningitis survivors

12.9% in base case and 22% in sensitivity analysis

Jit et al 24 and Ostergaard et al. 26

Average cost of treatment for neurological sequelae, per year

e35,000

Beutels et al. 38

and

31

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